Alkoxy substituted benzaldehydes of Formula I are an important class of compounds which find varied use in the chemical, agrochemicals, pharmaceutical and cosmetic industries, and these are also used as intermediates in the preparation of other known compounds. For example, 3,4-methylenedioxy benzaldehyde, also referred as heliotropin or piperonal, of Formula IV is used in fragrance and flavor applications, and also as an intermediate for the preparation of drug molecules such as Tadalafil™, as well as agrochemicals. Other examples include 3,4-dimethoxybenzaldehyde, 3,4,5-trimethoxybenzaldehyde and 3,4-ethylenedioxybenzene which are intermediates in the synthesis of active pharmaceutical intermediates. The required purity of the product depends upon the specific application; however it is preferable to have the material in substantially pure form (greater than 95%).
The conventional process for preparing heliotropin (piperonal), disclosed in the prior art comprises isomerizing and oxidizing safrole contained in the essential oil of Octoea Cym barum (disclosed in U.S. Pat. No. 2,916,499). However, this process has the drawback that the supply and the price of the raw material are unsteady due to its dependence upon the natural resources. Hence processes based on synthetic raw materials are preferable.
There are various chemical methods disclosed in the prior art for the synthesis of alkoxy substituted benzaldehydes.
Japanese patent application 156867/77 discloses a process for the preparation of heliotropin, comprising formylation of methylenedioxybenzene using N-methyl formanilide. However, 50 to 60% of 1,2-methylenedioxybenzene is recovered, and the energy consumption is very high, and therefore this is not advantageous as an industrial process.
J. Gen. Chem 8, 975 (1938) and British Pat. 1538214 disclose chloromethylation process for the preparation of heliotropin comprising chloromethylation of methylenedioxybenzene to obtain 3,4-methylenedioxybenzyl chloride which in turn is reacted with alkali metal salt of 2-nitropropane to obtain heliotropin. The yield of end product is 55-60% based on methylenedioxybenzene and also a large amount of tar like material is formed as a byproduct.
BE877911A1 discloses a process for converting methylenedioxybenzene into mandelic acid which in turn is converted into the corresponding benzaldehyde. The yield obtained is very low.
U.S. Pat. No. 4,942,240A discloses a process for the preparation of benzaldehyde and analogues thereof comprising reacting aromatic halide with a mixture of hydrogen and carbon monoxide in the presence of a noble metal based catalyst.
U.S. Pat. No. 4,605,749A discloses a process for the preparation of aromatic aldehydes wherein corresponding aryl halide is used as a starting material. Process disclosed therein comprises reacting aryl halide with carbon monoxide at super atmospheric pressure in the presence of a hydrogen donor, base and a catalyst.
U.S. Pat. No. 4,335,263A discloses a process for the preparation of aromatic aldehydes wherein a substituted benzyl halide obtained as an intermediate is converted into corresponding benzaldehyde by oxidizing the said benzyl halide. The process disclosed therein comprises of multiple steps for the preparation of methylenedioxybenzyl halide and the end product obtained is in 55.8% yield based on w/w in respect of methylenedioxybenzyl bromide. There is no mention of purity and yield of heliotropin.
JP3282338B2 discloses a process for the preparation of heliotropin wherein methylenedioxybenzyl chloride is oxidized with a hypohalogenous acid in the presence of a phase transfer catalyst in a two-phase system of an organic solvent and water.
JP62005977A also discloses the process for the preparation of heliotropin by electrolyzing methylenedioxybenzyl chloride by using an electrolyte like sodium hydroxide.
U.S. Pat. No. 8,618,335 discloses a process for preparing an aromatic aldehyde compound by reacting the corresponding aromatic methyl alcohol with peroxide in the presence of metal compound of tungsten or molybdenum, and either a quarternary ammonium salt or organic phosphonium salt.
JP54135770 discloses a process for the preparation of heliotropin comprising reacting methylenedioxybenzene with formaldehyde and HCl to obtain methylenedioxybenzyl chloride which is isolated and reacted with hexamethylenetetramine using chloroform as a solvent to obtain a salt also referred as complex. The said salt is isolated by filtration process and after dissolving in acetic acid is reacted with ammonia to obtain heliotropin. There is no mention of purity of the product obtained there from. The process disclosed in said patent comprises multiple operations such as solvent recovery and isolation/purification of intermediates, after each reaction step and also requires the use of more than one solvent, and requires the use of industrially unsafe chloroform as a reaction medium. There is no mention of the purity of the final isolated product.
WO2008023836 discloses a process for the preparation of heliotropin comprising reacting methylenedioxybenzene with formaldehyde and aqueous HCl in toluene to obtain piperonyl chloride in 85% yield based on internal online GC standard without mention of yield of isolated material. The solvent is distilled off and the said piperonyl chloride is reacted in a second reaction medium of acetic acid with hexamethylenetetramine in molar ratio of 0.25 moles to 1.0 mole per mole of piperonyl chloride to obtain the complex of Formula A which is subsequently decomposed to obtain piperonal. The piperonal obtained is isolated by extraction with ethyl acetate. The process disclosed therein involves the use of multiple solvents, as well as isolation/purification at intermediate stages. Moreover, the purity of the final product obtained is not mentioned.
All the processes disclosed in the prior art and described hereinabove require multiple unit operations such as solvent recovery and/or isolation/purification of intermediates, or are otherwise unsuitable for large-scale industrial production. This necessitates the development of an improved process for the preparation of alkoxy substituted benzaldehydes which minimizes the number of unit operations, provides better yield and higher purity of product and minimizes the solvent usage in comparison with the processes disclosed therein in the prior art, and which is suitable for industrial scale preparation of alkoxy substituted benzaldehydes.
The object of the present invention is to provide a solution to the technical problems associated with the prior art. Keeping the said object in view, the present invention provides an industrially viable and economical process thereby eliminating the above-mentioned shortcomings associated with the processes disclosed in the prior art for the preparation of alkoxy substituted benzaldehydes of Formula I.